Production of pyridazone derivatives



United States Patent C F PRODUCTION OF PYRIDAZONE DERIVATIVES Kaethe Bartram, Ludwigshafen (Rhine), Germany, as signor to Badische Anilin- & Soda-Fabrik Aktiengesellschaft, Ludwigshafen (Rhine), Germany No Drawing. Application May 1, 1956 Serial N0. 581,850

-' 5 Claims priority, application Germany May 7, 1955 7 Claims. c1. zen-247.5)

-.This invention relates to an improved process for the production of new pyridazone derivatives.

We have found that new, therapeutically valuable pyridazone derivatives are obtained by reacting beta-propionylpropionic acid with phenylhydrazine, treating the resultant 2-phenyl-6-ethylpyridazinone-(3) with a halogenating agent and allowing a secondary amine to act on the 4-halogen-2-phenyl-fi-ethylpyridazone-(3) thus obtained.

The reaction may be formulated as follows:

As secondary amines (HNR there may be used for example lower dialkylamines such as dimethylamine, diethylamin'e, methylethylamine, di-isopropylamine, pyrrolidine, piperidine, morpholine or hexamethylene imine.

The beta-propionylpropionic acid serving as initial material is accessible technically by catalytic reaction of 2 mols of ethylene with 2 mols of carbon monoxide and 1 mol of water by the processes described in U. S. Patent specification Nos. 2,562,393 and 2,577,208.

The reaction of this gamma-keto acid with phenyl hydrazine is effected by heating about equimolecular amounts of the components, preferably in an indifferent solvent, such as benzene, toluene or chlorbenzene. An addition of a basic agent, such as pyridine or triethanolamine, promotes the reaction and increases the yield of 2-phenyl-6-ethylpyridazinone- 3 This compound is then treated, preferably in an inert diluent, suchas chlorbenzene or phosphorus oxychloride, with a halogenating agent, dehydrogenating halogenation thus taking place. As halogenating agents there are suitable for example excess phosphorus pentachloride or pentabromide for example 3 to 5 mols thereof or free chlorine or bromine in the presence of catalytic amounts of the said phosphorus halides. It is preferable to add also an aluminum halide, for example 0.5 mol thereof. The 2-phenyl-6'ethyl-pyridazinone-(3) may also first be dehydrogenated for example with chlorine, bromine or sulfuryl chloride without the addition of phosphorus pentahalide to form 2-phenyl-6-ethylpyridazone-(3), the latter then being subjected to substituting halogenation,

2,824,873v Patented Febi2 5, '1958 ice.

for example with phosphorus pentachloride or with chlorine in the presence of a small amount of phosphorus pentachloride.

The reaction of the 4-halogen-2-phenyl-6-ethylpyridazone-(3) thus obtained with the said secondary amines already takes place rapidly and smoothly at room temperature. It is preferable to work in a solvent, such as methanol. To bind the hydrogen halide split off, a basic agent is added, such as triethylamine or pyridine;

w an excess of the secondary amine may also be used.

Y -(3) is obtained (E. Fischer, Liebigs Ann. Chem. 236,

147; yields of only about 60% of thetheoretical yield are obtained. From Z-phenyl-6-methyl-pyridazinone-(3), by fusion with phosphorus pentachloride, 4-chlor-2- phenyl-6-methylpyridazone-(3) has beenprepared in a yield of to of the theoretical yield (Ach,

LiebigsAnn. Chem. 253, 47), and this has been reacted with dirnethylamine to form 4-dimethylamino-2- phenyl-o-methyl-pyridazone-(3) (British patent specification No. 656,228). ,The process according to this invention, which starts from the more readily technically accessible beta-propionylpropionic acid, yields the hitherto unknown 6-ethyl-4-amino-2-phenyl-pyridazone-(3) in better yields; the pharmacological properties of the new pyridazone derivatives are superior'to those of the prod- -uct known from the British patent specification No.

The following examples will further illustrate this invention but the invention is not restricted to these examples. The parts specified are parts by weight.

Example 1 is diluted with ether and the ethereal solution washed with water.

After evaporating the. ether, the whole is fractionally distilled under reduced pressure. The main fraction passes over at 165 to 171 C. under a pressure of 2 Torr. parts of Z-phenyl-6-ethylpyridazinone-(3) are obtained.

A solution of 300 parts of this product in 330 parts of chlorbenzene is introduced while stirring intov a sus pension of 1,500 parts of phosphorus pentachloride in 550 parts of chlorbenzene which has been heated to 70 to C. The mixture is heated in the course of 30 minutes to C., about 300 parts of phosphorus trichloride thus distilling off. The reaction mixture is then poured onto about 4,000 parts of ice and extracted with ether. After distilling off the ether and the chlorbenzene the residue is boiled up with cyclohexane. By cooling the cyclohexane solution, Z-phenyl-6-ethyl-4-chlorpyridazone-( 3) crystallizes out; it can be purified by recrystallization from cyclohexane or from a mixture of water and alcohol. It melts at 79 to 81 C. The yield amounts to 220 parts (64% of the theoretical yield).

parts of 2-phenyl-4-chlor-fi-ethylpyridazone-(3) are boiled under reflux for 24 hours with 90 parts of pyrrolidine in 350 parts of toluene. After cooling, the precipitated pyrrolidine hydrochloride is filtered off by suction and the toluene distilled off under reduced pressure. The residue is washed with water and distilled.

The i2 plienylf4-pyrrolidino-fi-ethylpyridafzone 'fi)"passes iover at 2 1 5? to 220? Q at a pressure of,4,Torr.; ILsolidi I fies to crystals melting'at 5810 59 C; Theyield amounts to IIO parts. V I V i ss mn i i ether; The dimeth yla mine hydfochloridethereby {separatingisfilteredfofi by suction and the ether evaporated;

' 'The residue; cflnsisting'of 2-phenyl 4-dimethylamino{6- 'ethylpyrida'zone-(fi), yields crystals melting at 52213 53? C. after recrystallization from 'cyclohexane or-trom-a mixture of alcohol and waterb A pharmacological comparison of sZ-phenyl LdimethyI- i amino-fi-ethylpyridazone-(3) with the known' 2-sphenyliglimethylaminofi-methylpyridazone- (3.) gavethe-foll'owing'resultsr a r In an analgesic test on mice :(heat mange-deified); V q the normal reaction time of the'mice' waspi plongedj by the followingmaximumvalues: a j;:

moment of highest 'feveri'the-relative fall in temperatui'e 40 produced by mgJkg. 'was -lL- C. with the 6-ethyl derivative as compared'with=-0.8 C. vvith-the known 6-methy1-derivative.; J

jrn'e 'f 2-phenyl d-chlor-6 e 'i iidazbne cy qbt aine df'. according .f .to Example! 1; is I reacted \yitli heiiilnethy lene imine as in Example 1. Z- hen'yI-4-hexamethylenein1ino Cat a pressure of 1 Torr. is thereby obtained. a

rated at feiiueed pr up with ice. After standing 7 V f s e tedintegi tifi r ys ai nuln Jot12-pheny1-4:eh1nr-6-"' erystalsiatthemelting point 78 to 79."

' V Example 4 i A solution of 75 parts of"2-phenyl-6-ethy1pyridazinone (3) prepared according to; paragraph' l of Example 1 in t j l t a hlq e ha s ows d to flew M17939 F w est e -ree s n to7120 a thereby beingdi d 01? e' product is F ethylpyridazone ljy gvhich is filterdpfi by suction and washed with Wairb TheyielG amofin t's tens parts. The a V reaction with amines, such as pyrrolidine, dimethylamine s s V morpholinegoridiethylamine, is effected asizin theipre'Ce dr J J;

ing examples r nl'claim: "1; i

. 1. lPyridazonederivativesr ofthe general formula'i V V hi ing w in which NR is the; radigal .oflasatnrated secondary V V amine, the two R together having a sequence of from a to 6 members. s V i a 7 M 2. Pyridazone derivatives asclaimed in claim "1 wherein -NR' stands for THfliF-X-llf H,oc? 1cm L a X being -QICH andon ygeng v 3. 2-phenyl-4-pyrrolidino-6-ethylpyridazone-(3)Q 7 4. 2 -phenyl 4 dimethylamino-6-ethylpyfiglazone-(3). 5. 2-phenyl 4-hexamethyleneimino6 ethy1pyridazone-' 6. '2-phenyl-4-morpholino 6-ethylpyriiiazone (3 1 .77.: 2-phenyl-4aethylamino-fi-ethylpyridazinonef(3); 

1. PYRIDAZONE DERIVATIVES OF THE GENERAL FORMULA 